Dr. Elizabeth G Ingulli is pediatrician who is currently in a fellowship training program at the University of Minnesota. The candidate's long- term goal is to pursue an academic career devoted primarily to basic research. The candidate's interest in research began in medical school and focused on childhood nephrotic syndrome and renal transplantation. A lack of an understanding of the basic mechanisms of allograft rejection has led the candidate to take a more fundamental approach to better understand disease processes. The proposed funding. The rich academic and research environment at the University of Minnesota is extremely well- suited for the candidate's career development. The candidate will investigate the earliest events of antigen presentation and will focus on the interaction between dendritic cells and T lymphocytes in an in vivo system. CD4+ T lymphocytes play a central role in the development of immune responses against pathogens and are central players in autoimmune diseases as well as in graft rejection. In vitro studies indicate that in order for CD4+ T lymphocytes to produce lymphokines and proliferate in response to foreign proteins, two biological signals are required. One signal results from T cell receptor (TCR) occupancy by peptide/major histocompatibility complexes expressed on the surface of antigen presenting cells (APC). The other signal is provided by the interaction of CD28 receptor (present on all T cells) with its ligand, B7, expressed on professional APC. To study CD4+ lymphocytes in vivo, we recently developed an animal model that enables us to track ovalbumin peptide- specific CD4+ T lymphocytes during the course of an immune response. In this proposal, we describe a second system that allows us, for the first time, to directly visualize ovalbumin peptide/MHC-bearing APC (dendritic cells) along with the ovalbumin peptide-specific T cells in vivo. Using this system we will analyze in great detail the cellular and molecular events that mediate the interaction between T cells and APC. Additionally, we will manipulate this interaction with the goal to alter the T cell response. of particular interest is the exploitation of the B7/CD28 pathway in inducing tolerance. TCR occupancy in the absence of B7/CD28 costimulation induces a state of unresponsiveness that has been suggested to account for tolerance in vivo. We propose to investigate the role of B7/CD28 interaction in this in vivo system. Understanding the events that regulate CD4+ T cell activation in vivo, is crucial for the development of new therapies to prevent unwanted immune responses such as allograft rejection.